Cryptococcus neoformans endocarditis in an immunocompetentpatient a case report

Background Cryptococcus neoformans is an invasive fungal infection commonly affecting immunocompromised patients as pneumonia or meningitis. More rarely, case reports describe Cryptococcus neoformans endocarditis, though nearly exclusively among patients with active immunosuppression, implanted cardiac devices or prosthetic valves. Case presentation We report the case of a patient with underlying substance abuse disorder and systolic heart failure presenting with fever, altered mental status, and shower emboli subsequently found to have native tricuspid valve vegetations and blood cultures positive for cryptococcus neoformans in the absence of immunosuppression. Conclusions Historically, Cryptococcus neoformans fungemia manifests clinically as pneumonia or meningitis among the immunosuppressed. There have been rare reports of endocarditis in this population and even fewer reports of native valve endocarditis exist. The present case along with mortality reported in prior literature, suggest suspicion must be maintained in the absence of immunosuppression, even in patients with native valves.

Keywords: Cryptococcal endocarditis, Cryptococcal fungemia cardiac manifestations, Cryptococcal infection in heart failure, Cryptococcus neoformans valvular disease Background Cryptococcus neoformans (CN) is an encapsulated yeast found throughout the world known to cause nearly half a million deaths per year. Immunocompromised patients are predominantly affected [1,2]. Most commonly, CN presents as pneumonia or meningitis though rare cases of infective endocarditis are described [3,4]. Current literature posits a majority of the CN endocarditis in nonimmunosuppressed patients in association to implanted cardiac devices and prosthetic valves [5]. Herein, we describe the novel presentation and clinical course in an immunocompetent patient with native heart valves.

Case presentation
A 65-year-old female with a past medical history significant for heart failure with reduced left ventricular ejection fraction, chronic obstructive pulmonary disease, stage III chronic kidney disease and substance abuse disorder presented with altered mental status. On presentation, she had notable bilateral conjunctival hemorrhages, splinter hemorrhages, and signs of hypervolemia to include jugular venous distension and pitting edema of both lower extremities. "Track marks" were evident in the cubital fossa along with scattered hyperpigmented ovaloid lesions consistent with "skin popping" injuries. Admission laboratory results showed elevated blood urea nitrogen 65 mg/dL, hyperkalemia of 6 mmol/L, acute kidney injury (creatinine of 4.93 mg/dL from baseline 1.57 mg/dL) and a urinalysis consistent with urinary tract infection, white blood cell count showed no leukocytosis (WBC 5.6 k/uL), hemoglobin showed anemia (Hgb 10.8 gm/dL), platelets were 172 k/uL, a coagulopathy with prothrombin 16.7 s, international normalized ratio 1.9, liver function showed aspartate aminotransferase of 48 units/L, alanine transaminase 21 units/L, and elevated high sensitivity troponin I 838 ng/L which decreased over the following hospital days. Further, the patient was COVID-19 positive. Dexamethasone, remdesivir, and aztreonam were given at initial presentation. Her urine cultured positive for Proteus mirabilis (10,000 to 100,000 cfu) and antibiotics were narrowed to reported sensitivity on hospital day 2. Nonetheless, she persistently reported chills and demonstrated continued alteration of mental status. Blood cultures were negative.
A transthoracic echocardiogram completed on hospital day 3 for her volume overload and acute decompensated heart failure highlighted interval worsening of her moderate-severe aortic regurgitation and new small mobile echo densities on the ventricular side of the aortic valve, suspicious for vegetation (Fig. 1). Computed tomography of the head on hospital day 3 revealed several foci of hypodensity in the frontal and parietal lobes, confirmed by immediate follow-up  MRI to indicate acute infarcts (Fig. 2). Concern for other embolic phenomena prompted CT of the chest, abdomen, and pelvis which returned positive for new nodular density in the left lower lung lobe (Fig. 3) and scattered hypoattenuating nodules in the liver (Fig. 4). An abnormal signal in the pancreatic head not amenable to characterization beyond mass versus embolic sequalae was also noted. Heparin infusion was initiated given a concern for diffuse emboli. A week after admission, blood culture resulted positive for cryptococcus. Anti-fungal coverage with micafungin and flucytosine was initiated immediately. On hospital day 11 the patient developed thrombocytopenia (platelet count 30 k/uL) and heparin infusion was ceased for possible heparin induced thrombocytopenia. Positive Duke's criteria in the patient included (1) evidence of endocardial involvement on echocardiogram, (2) predisposing risk factor (IVD's), (3) presence of vascular phenomenon (conjunctival and splinter hemorrhages, septic pulmonary infarct, cerebral emboli) and (4) blood culture positivity. Serum cryptococcal antigen titers returned 1:256 on hospital day 12. After positive antigen titers, Amphotericin was added to flucytosine. On hospital day 13, lumbar puncture revealed an opening pressure of 26 mmHg, glucose 71 mg/dL, protein 32 mg/dL, and lymphocytes 79 microL. Cerebrospinal fluid culture was completed and negative as were Human immunodeficiency virus (HIV) and immunoglobulin panels. Transesophageal echocardiogram was planned for hospital day 17 but the patients worsening mixed septic and cardiogenic shock resulted in respiratory and hemodynamic failure causing death.

Discussion
Rates of fungal endocarditis rate are rising and are estimated to comprise 1-10% of all infective endocarditis with a total of 1.5 to 11.6 cases per 100,000 [6]. The most common fungal infection is Candida albicans (24-46%), followed by Aspergillus (25%) [7]. Fungal endocarditis is typically a progression from initial fungemia when the cardiac valves are seeded. A prominent risk factor among non-immunocompromised hosts is IV-drug use [8].
More frequently, CN infections affect immunocompromised patients. Incidence is 2-7 per 1000 among    HIV positive patients in the United States and confers substantial mortality risk at a rate of 12% [9]. Epidemiology of non-immunocompromised hosts and the underlying infection rates of CN is elusive and less clear [10]. The most common underlying risk factors have been described as diabetes mellitus, end-stage renal disease, liver cirrhosis, and IV-drug use [8,10]. Non-immunocompromised patients have proportionately less CNS involvement and cryptococcemia compared to immunocompromised patients [10]. CN heart disease is previously reported as presentation of mycotic endocarditis, pericarditis, and cardiomyopathy [5,11,12]. Many prior cases have involved implantable prosthetic cardiac devices (prosthetic valves or AICD's). Patients without implanted devices are frequently immunosuppressed. Only 2 prior cases describe patients void of active immunosuppression and implanted cardiac devices. Among these, IVD use is a unifying risk factor [4,5,[13][14][15][16][17][18][19][20][21].Diagnosis of fungal endocarditis historically hinges on the Duke Criteria which may preclude a diagnosis if the infection is caused by nontypical microorganisms. In this vain, it remains imperative for the clinician to maintain high index of suspicion in patients with risk factors [22]. In cases of CN endocarditis, a majority of blood cultures will return positive (Table 1). Table 1 summarizes characteristics in the previously available literature CN endocarditis cases. Patient age ranges 4 years to 65 years old. 10 males and 2 females have been affected. Common symptoms at presentation include fever, pulmonary complaints, and delirium. The most common comorbidities include chronic kidney disease, immunosuppression, valvular disease and intravenous drug use. Immunosuppressed patients are more often infected. Non-suppressed patients frequently had prosthetic heart valves. To date, only the aortic and mitral valves have been implicated. 3 cases of immunecompetent patients without a prosthetic valve are known. Treatment has included amphotericin B. in every case. Common medical complications include meningitis and cerebral infarction. Death occurred in 5 out of 12 cases.

Acknowledgements
There are no further acknowledgements for the present study.
Author contribution CM and DW jointly co-authored the article. CM, DW and SW independently analyzed and compiled findings of the cited literature reviews. All parties are agreement and consent for publication of information contained within the report. All authors read and approved the final manuscript.

Funding
The present report was generated without funding.

Availability of data and material
All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Declarations Ethics approval and consent to participate
This article complies with Georgetown University Ethical Code of Conduct and appropriate steps for identity protection have been taken per guidelines of the office of Regulatory Affairs.

Consent for publication
Consent for publication of laboratory findings and diagnostic imaging, along with all clinical documents related to the present case was obtained from medical power of attorney in written form, available upon request.